JPWO2010010909A1 - Chronic renal failure treatment - Google Patents

Abstract

An object of the present invention is to provide a therapeutic agent for chronic renal failure containing a compound represented by the general formula (1) or a pharmacologically acceptable salt thereof as an active ingredient. That is, the present invention comprises a compound represented by the general formula (1) or a pharmacologically acceptable salt thereof as an active ingredient, not only improving renal function, but also improving anemia, activating SOD and uremic substances. It is provided to provide a drug that can be excreted.

Description

The present invention relates to an agent for treating chronic renal failure having a non-prostanoid skeleton and comprising a PGI ₂ receptor agonist as an active ingredient.

  In recent years, the number of patients who are forced to introduce dialysis due to decreased renal function has been increasing. The reasons for this include changes in living environment and aging, as well as an increase in diabetic nephropathy accompanying the recent increase in diabetic patients.

  Renal failure refers to impaired renal blood flow, decreased functional nephron, and obstruction of the urinary tract, resulting in inadequate excretion of nitrogen metabolites, water, and electrolytes, and inability to maintain quantitative and qualitative homeostasis of body fluids. State. Renal failure includes acute renal failure and chronic renal failure, both of which have common features that blood urea nitrogen (BUN) and serum creatinine levels increase, but the speed of progression of the disease state and decrease in renal function There is a big difference in reversibility, clearly a different disease. Acute renal failure develops rapidly and progresses on a daily basis (serum creatinine level increases by 0.5 mg / dL or more per day as a guideline), but the cause is removed and sufficient systemic management is performed to provide conservative therapy and dialysis therapy. By appropriately carrying out the above, basically, recovery of renal function can be expected (Non-patent Document 1). On the other hand, it takes a long time to establish chronic renal failure. That is, when renal diseases that cause glomerulonephritis, diabetic nephropathy, and the like gradually progress year by year, and BUN and serum creatinine levels clearly increase, it is determined that chronic renal failure has occurred. At this point in time when an increase in serum creatinine level is observed, the filtration function of low molecular weight waste, which is the most important function played by the kidney, is significantly reduced, and the glomerular filtration rate is 50% or less. The decline in function is irreversible. Even after chronic renal failure is established, the decrease in renal function gradually progresses over several years, and when glomerular filtration rate becomes 10% or less, it becomes end-stage chronic renal failure requiring dialysis or kidney transplantation. For this reason, in the treatment of chronic renal failure during the preservation period, it is important how to delay the period until dialysis (Non-patent Documents 2 and 3).

  Causes of chronic renal failure include primary kidney disease, systemic kidney disease, congenital kidney disease, kidney infection, nephrotoxic substance-induced kidney injury, and urinary obstruction disease . Among these, the main causative diseases include chronic glomerulonephritis, diabetic nephropathy, chronic pyelonephritis, nephrosclerosis, cystic kidney and the like. Among them, the ratios of chronic glomerulonephritis, diabetic nephropathy and nephrosclerosis are high, but with the rapid increase in the number of diabetic patients in recent years, the cause of chronic renal failure due to diabetic nephropathy is markedly increasing.

  In chronic renal failure, pulmonary congestion and congestive heart failure associated with decreased urine output, neurological and psychiatric symptoms associated with progression of uremia, anemia due to decreased erythropoietin produced in the kidney, hyponatremia and hyperkalemia In addition to electrolyte abnormalities such as gastrointestinal symptoms, bone metabolism abnormalities, sugar metabolism abnormalities, etc., common clinical symptoms are seen in chronic renal failure regardless of the causative disease.

  Chronic renal failure is thought to have a common mechanism of progression independent of the underlying disease. For example, a general textbook of internal medicine also states, “In general, chronic renal failure shows progression of chronic renal failure even when the primary disease seems to have subsided. It is considered that there is a mechanism of reduced renal function ”(Non-patent Document 4).

  Furthermore, it is known that chronic renal failure exhibits common clinical symptoms even if the underlying disease causing it is different. In other words, most chronic renal diseases, whether primary (primary) or secondary (secondary), have an irreversible decline in renal function as the disease progresses. `` This condition eventually leads to a kind of syndrome called uremic disease, but in this case there is little difference depending on the type of underlying disease, and it shows common clinical symptoms. '' (Non-Patent Document 5).

  The renal pathological findings also indicate that the kidneys of patients with end-stage chronic renal failure show a common histology in many cases even if the underlying disease is different, and it is difficult to diagnose the underlying disease pathologically. Many ”(Non-Patent Document 6).

  As described above, the diseases causing chronic renal failure are diverse, but they exhibit characteristic clinical symptoms that are different from those of other renal diseases, have a common mechanism of progression of the disease state, and pathological findings. Because it has characteristic findings that do not reflect the underlying disease, and the treatment method also requires a treatment method specific to chronic renal failure, chronic renal failure is distinguishable from other renal diseases. Is a common disease.

  Treatment of chronic renal failure is based on a diet that consists of a low-protein, high-calorie diet as a treatment in the preservation period before dialysis. Restriction of salt and water, and use of antihypertensive agents is performed. Oral activated charcoal preparations may be used to delay the progression of the disease state or to improve uremic symptoms. However, even with these treatments, the progression of the disease state cannot be sufficiently prevented, and the number of patients forced to undergo hemodialysis has been increasing due to the appearance of uremic symptoms due to the progression of renal dysfunction. ing. In patients with chronic renal failure who have transitioned to dialysis, improvement in the survival rate has been obtained due to recent advances in hemodialysis, but not only two to three visits per week are required, but long-term Many issues remain, such as the emergence of complications associated with dialysis, increased risk of developing infections, cardiovascular disorders, and rising medical costs. In particular, when dialysis is caused due to diabetic nephropathy, the 5-year survival period is only 50% or less (Non-patent Document 7).

  As described above, various complications characteristic of chronic renal failure occur in patients with chronic renal failure. Of particular concern is anemia that develops and worsens with decreasing renal function. Anemia begins to appear when blood urea nitrogen (BUN) and blood creatinine levels begin to rise, and almost all patients with end-stage chronic renal failure, such as dialysis, develop reduced willingness to work, fatigue, shortness of breath, It significantly reduces the patient's QOL, such as standing dizziness.

  For the treatment of anemia associated with chronic renal failure, blood transfusion has been performed in the past, but at present, treatment with a recombinant erythropoietin preparation (rHuEPO preparation) is widespread. However, treatment with this preparation requires hospital visits, and it is pointed out that it is painful because it is administered subcutaneously, and that there are drug-resistant patients due to the appearance of autoantibodies. Therefore, a prophylactic or therapeutic agent for anemia associated with chronic renal failure that is easy to administer, can be administered at home, and has no side effects is desired.

In recent years, the importance of active oxygen has been pointed out for the progression of chronic renal failure and the exacerbation of complications associated with chronic renal failure. Superoxide dismutase (hereinafter sometimes abbreviated as SOD) is widely distributed in living bodies such as animals, plants, and microorganisms, and is a superoxide anion radical (hereinafter abbreviated as O ₂ ⁻⁾ which is a reactive oxygen rich in reactivity. It is particularly important among the enzymes that break down. In chronic renal failure, SOD activity in the kidney or liver is decreased, and this decrease is deeply involved in the onset and exacerbation of chronic renal failure complications such as decreased renal function due to active oxygen and cardiovascular disorders (Non-Patent Document 8).

  In chronic renal failure, low molecular weight substances (uremic substances) that accumulate in the body with decreased renal function cause clinical symptoms peculiar to chronic renal failure, leading to exacerbation of cardiovascular disorders and further decline in renal function . Indoxyl sulfate is a low-molecular substance produced by indole produced from tryptophan in the intestine and then metabolized in the liver after being absorbed into the living body. Since indoxyl sulfate is mainly excreted from the kidney, in chronic renal failure, it cannot be efficiently excreted due to a decrease in renal function, and the blood concentration increases. In recent years, indoxyl sulfate has attracted attention as one of the causative substances of exacerbation of various complications of chronic renal failure and cardiovascular disorders due to endothelial damage (Non-patent Document 9). It is also known that indoxyl sulfate itself is involved in exacerbation of kidney damage (Non-patent Document 10).

  It is known that indoxyl sulfate is actively excreted from the tubule actively through the organic anion transporter OAT-3 present mainly in the renal tubule, and that OAT-3 is decreased in chronic renal failure. (Non-Patent Document 11).

  Furthermore, it is known that in chronic renal failure, blood concentrations of various drugs, particularly renal excretion-type drugs, are likely to increase as compared with healthy individuals. For this reason, patients with chronic renal failure often experience increased side effects of the drug, and it is often difficult to set appropriate doses. One of the mechanisms is a decrease in drug transporters in the kidney. Is involved.

  Thus, in the treatment of patients with chronic renal failure, not only the decrease in the low molecular filtration function of the kidney is suppressed, but also how to suppress anemia and increased active oxygen associated with chronic renal failure, The problem is how to prevent the drop in transporters that accompanies this.

Prostaglandins (PGs) are a group of compounds that exhibit a variety of naturally occurring physiological activities and have a common prostanoic acid skeleton. Naturally occurring PGs are classified into PGAs, PGBs, PGCs, PGDs, PGEs, PGFs, PGGs, PGHs, PGIs, PGJs according to the structural characteristics of the five-membered ring. Further, it is classified into subclasses 1, 2, 3, etc. depending on the presence of unsaturation and oxidation. Many of these synthetic analogues are also known. Among PGI derivatives, typical PGI ₂ is also called prostacyclin, and is known as a substance having a strong platelet aggregation inhibitory action and a peripheral vasodilatory action.

It is already known that some compounds of PGI ₂ and its derivatives are effective in animal models of glomerulonephritis or diabetic nephropathy and clinical conditions. However, such findings from PGI ₂ or its derivatives are intended for primary diseases that do not lead to chronic renal failure. In this stage, kidney damage is evaluated by urinary protein, which increases due to a decrease in the barrier function of the polymeric substance in the glomerular basement membrane of the kidney, and urinary microalbumin. It is evaluated.

On the other hand, there are reports on the effectiveness of PGI ₂ derivatives in chronic renal failure (Patent Documents 1-10 and Non-Patent Documents 12-15). For example, the results of m-phenylene PGI ₂ derivative containing beraprost sodium in a rat model of renal renal failure whose primary disease is a nephritis produced by administering a partial nephrectomy model rat and an anti-basement membrane antibody have been reported ( Patent Document 1 and Non-Patent Document 12). In order to accurately evaluate renal function in chronic renal failure, glomerular filtration rate (GFR), which is a low molecular filtration function marker of kidney, or eGFR (estimated GFR: estimated glomerular filtration rate) or creatinine clearance is used as a substitute for it. In addition, serum creatinine value or BUN that increases with a decrease in renal low-molecular filtration function is used. In Patent Document 1 and Non-Patent Document 12, serum creatinine value and BUN are used as indexes as an evaluation of drug efficacy. That is, in this rat model, the administration of a compound of m-phenylene PGI ₂ derivative was started after the chronic renal failure defined by the serum creatinine level or BUN being higher than the normal level, and the serum creatinine level was started. It has been shown that an increase in a chronic renal failure marker called BUN value is suppressed as compared with the control group.

Non-patent document 13 describes that cicaprost, a PGI ₂ derivative, showed improvement in microalbuminuria in a canine mild chronic renal failure model, but GFR maintained 82% compared to normal. Evaluation with a model that has not reached chronic renal failure with a GFR of 50% or less. Also, the perceived effect is not an improvement in the renal low molecular filtration function, but merely a reversible change in microalbuminuria.

It has been reported that in patients with chronic renal failure, the rate of decrease in renal function indicated by the decrease in creatinine clearance and the inverse of serum creatinine level was suppressed by administration of beraprost sodium (Non-Patent Document 14). It has been described that treprostinil, a PGI ₂ derivative, has improved renal function as seen in urine production in patients with chronic renal failure. It has not been clarified (Patent Document 2).

In the case of hypoxemia, there is a possibility of promoting erythropoietin production through an increase in endogenous PGE ₂ and PGI ₂ production in the kidney (Non-patent Document 15). In chronic renal failure, since there is a hypoxic state of the kidney, high anemia is a problem despite the production of endogenous PGE ₂ , PGI _{2 and} even erythropoietin. The reason for this is unclear, but it is considered that the anemia-improving action based on the mechanism based on this document may not function sufficiently in renal failure.

The anemia improvement of PGI ₂ or its derivative, a result of the improved anemia in long-term dialysis patients with peripheral circulatory disorders have been reported only for beraprost sodium (Non-patent Document 16). However, this document is an improvement in anemia in long-term dialysis patients where most kidney cells have lost their original function. The improvement of anemia in the rat model of chronic renal failure of the present application is an improvement of anemia in conservative chronic renal failure in which renal cell functions are partially maintained, and the pathological conditions are different. Therefore, from this document, the degree of the effect of beraprost sodium in the conservative chronic renal failure could not be predicted, and there was no disclosure, and it was not possible to infer a significant difference in the effect between the PGI ₂ derivatives. In addition, beraprost sodium has been reported to improve uremia in patients with chronic renal failure. Although anemia is described as one of the specific complications of uremia, there is no description about a specific anemia improving effect by beraprost administration (Patent Document 3).

In addition, administration of PGI ₂ or a derivative thereof increases SOD activity in erythrocytes in rat gastric mucosa, human systemic sclerosis patients having Raynaud's symptoms (Non-patent Documents 17 and 18), and the target organs and diseases are completely absent. in different chronic renal failure, whether to increase the renal SOD activity, for whether or not there is a difference in the effect between PGI ₂ and derivatives thereof, are not whatsoever nor suggested it said. Furthermore, it has not been known to suppress a decrease in renal organic anion transporter in renal failure.

Cicaprost, m-phenylene PGI ₂ derivatives, particularly beraprost sodium, and treprostinil, which are compounds used in the above-mentioned literature, are all PGI ₂ derivatives with improved instability of natural PGI ₂ .

In contrast, recently, PGI ₂ receptor agonists having a non-prostanoid skeleton have been developed.

  Of these, the following general formula

The compound represented by PGI ₂ receptor has an antiplatelet action, a vasodilator action, a bronchodilator action, etc., and also has a transient cerebral ischemic attack, diabetic neuropathy, diabetic gangrene, The possibility of being useful for diseases such as peripheral circulatory disorders has been pointed out. Moreover, in the Example of the same patent document, it has been confirmed that it has an antiplatelet action which serves as an index of PGI ₂ receptor operability. In this patent document, it is described that the compound represented by the above general formula is useful as a therapeutic agent for glomerulonephritis and diabetic nephropathy, as well as other PGI ₂ receptor agonists (patents). Reference 4).

  However, it is not described at all that the compound represented by the above general formula is characteristic and markedly effective as a therapeutic agent for chronic renal failure among renal diseases.

Furthermore, Patent Documents 5 to 10 disclose that a PGI ₂ receptor agonist having a non-prostanoid skeleton can be used for renal failure, but it has characteristic and remarkable effectiveness particularly as a therapeutic agent for chronic renal failure. No mention is made of having

  That is, when these compounds are used as a treatment for chronic renal failure, they play a central role in improving renal low-molecular filtration function, improving anemia as a complication of chronic renal failure, and removing active oxygen. There is no description or suggestion about increasing the SOD activity that bears urine and suppressing the decrease in renal organic anion transporter that actively excretes uremic substances.

International Publication No. 2000/067748 Pamphlet International Publication No. 2005/058329 Pamphlet International Publication No. 2007/007668 Pamphlet International Publication No. 2002/088084 Pamphlet International Publication No. 1997/03973 Pamphlet International Publication No. 1999/21843 Pamphlet International Publication No. 1999/32435 Pamphlet International Publication No. 2001/016132 Pamphlet International Publication No. 2004/034965 Pamphlet JP 2000-191523 pamphlet

Kenjiro Kimura et al., Lectures Nephrology 1st edition Medical View Company 2004 Page 270 1st to 10th lines Kenjiro Kimura Others, Lectures Nephrology 1st edition Medical View, Inc. 2004 Pages 274 to 275 Minamigaku Masaomi Japanese Pharmacology 118: 68-70.2001 Hyper Clinical Internal Medicine Nakayama Shoten 1997 Kurokawa Kiyoshi Approach from Nephrology Pathophysiology Nanoedo 1995 Page 345 Left column 1st to 7th lines Kurokawa Kiyoshi Approach from Nephrology Pathophysiology Nanedo 1995, page 347, left column, 3rd to 5th line Villar E, et al., J Am Soc Nephrol, 18: 2125-2134. 2007 Vaziri ND, et al., Kidney Int, 63: 179-185. 2003 Dou L, et al., Kidney Int, 65: 442-451. 2004 Enomoto A, et al., Ther ApherDial, 11 Supple 1: S27-31. 2007 Villar SR, et al., Kidney Int, 68: 2704-2713. 2005 Yamada M, et al., Eur J Pharmacol, 449: 167-176. 2002 Villa E, et al., Am J Hypertens, 6: 253-257. 1993 Fujita T, et al., Prostaglandins Leukot EssentFatty Acids, 65: 223-227. 2001 Kurokawa Kiyoshi Approach from the pathophysiology of nephrology Minamiedo 1995, pp. 48-49 Hidekazu Moriya Abstracts from the Japanese Society for Dialysis Therapy O-425 2006 Zsoldos T, et al., Acta Physiol Hung, 64: 325-330. 1984 Balbir-Gurman A, et al., Clin Rheumatol, 26: 1517-1521. 2007

  In patients with chronic renal failure, the filtration function of low molecular weight substances in the kidneys is irreversibly reduced. Therefore, it is required to slow down the rate of this decrease and to extend the period until the introduction of dialysis as much as possible. It also shows how to effectively prevent anemia of complications that develop with the progression of chronic renal failure and the increase in oxidative stress that causes cardiovascular and vascular endothelial cell damage associated with chronic renal failure. It has become a challenge. Furthermore, improvement of uremia caused by chronic renal failure, and the increase in the blood concentration of drugs and the difficulty of control seen in chronic renal failure are also problems. An object of the present invention is to provide a chronic renal failure treatment agent and a treatment method for improving these problems.

The above object is to provide a therapeutic agent for chronic renal failure having a non-prostanoid skeleton and a compound represented by the general formula (1), which is a PGI ₂ receptor agonist, or a pharmacologically acceptable salt thereof as an active ingredient. can be solved.

That is, the present invention
[1] The following general formula (1)

[Wherein R ¹ and R ² each independently represent aryl,
A represents NR ⁵ , O, S, SO or SO ₂ ;
R ⁵ represents alkyl having 1 to 6 carbons, alkenyl having 2 to 6 carbons or cycloalkyl having 3 to 6 carbons;
D represents alkylene or alkenylene having 2 to 6 carbon atoms,
G represents O, S, SO or SO ₂ ;
R ³ and R ⁴ each independently represent hydrogen or alkyl having 1 to 6 carbons,
Q is carboxyl, alkoxycarbonyl having 1 to 6 carbon atoms, tetrazolyl, or the following general formula (2)

(In the formula, R ⁶ represents alkyl having 1 to 6 carbon atoms.)
Represents. ]
Or a pharmacologically acceptable salt thereof as an active ingredient.
[2] R ¹ and R ² represent phenyl,
R ⁵ represents alkyl having 1 to 6 carbon atoms,
D represents alkylene having 2 to 6 carbon atoms;
G represents O,
R ³ and R ⁴ represent hydrogen,
Q represents carboxyl or general formula (2),
[1] The chronic renal failure treatment agent according to [1].
[3] A represents NR ⁵ ;
R ⁵ represents a branched alkyl having 3 to 6 carbon atoms,
D represents butylene,
Q represents carboxyl or general formula (2),
The therapeutic agent for chronic renal failure according to [1] or [2].
[4] R ⁵ represents isopropyl;
Q represents carboxyl or general formula (2),
The therapeutic agent for chronic renal failure according to any one of [1] to [3].
[5] Q represents carboxyl.
The therapeutic agent for chronic renal failure according to any one of [1] to [4].
[6] The chronic renal failure treatment agent according to any one of [1] to [5], wherein the chronic renal failure is conservative chronic renal failure.
[7] A therapeutic method for treating chronic renal failure using the compound according to any one of [1] to [5], or a pharmacologically acceptable salt thereof.

  It is.

The compound represented by the general formula (1) or a pharmacologically acceptable salt thereof (hereinafter sometimes referred to as “the compound of the present invention”) is administered after renal disease has progressed to chronic renal failure. By initiating, it is possible not only to suppress the decrease in the low molecular filtration function of the kidney but also to improve and restore it. Furthermore, in addition to improving anemia, which is a complication specific to chronic renal failure, it also has the effect of increasing SOD activity that decreases in chronic renal failure and suppressing the decrease in OAT-3 related to excretion of uremic substances. Can improve cardiovascular disorders and vascular endothelial cell disorders associated with chronic renal failure.

The serum creatinine value in the sodium salt administration group of the compound 1 using a chronic renal failure rat is shown. 2 shows BUN in a sodium salt administration group of Compound 1 using rats with chronic renal failure. The creatinine clearance in the sodium salt administration group of the compound 1 using a chronic renal failure rat is shown. 2 shows the plasma concentration transition of Compound 1 when Compound 1 and Compound 2 were orally administered.

  Examples of “aryl” in the compound represented by the general formula (1) include phenyl, 1-naphthyl, and 2-naphthyl.

  Examples of “alkyl having 1 to 6 carbon atoms” include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl and isohexyl. Can be mentioned.

  Examples of “alkenyl having 2 to 6 carbon atoms” include, for example, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4- Examples include pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl.

  Examples of “cycloalkyl having 3 to 6 carbon atoms” include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

  Examples of the “C 2 -C 6 alkylene” include ethylene, 1-methylethylene, 2-methylethylene, propylene, butylene, pentylene, and hexylene.

  Examples of the “alkenylene having 2 to 6 carbon atoms” include, for example, ethenylene, 1-propenylene, 2-propenylene, 1-butenylene, 2-butenylene, 3-butenylene, 1-pentenylene, 2-pentenylene, 3-pentenylene, 4- Examples include pentenylene, 4-methyl-3-pentenylene, 1-hexenylene, 2-hexenylene, 3-hexenylene, 4-hexenylene, and 5-hexenylene.

  The “C 1-6 alkoxy” of the “C 1-6 alkoxycarbonyl” includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, Examples include n-pentyloxy, isopentyloxy, n-hexyloxy, and isohexyloxy.

  As the “pharmacologically acceptable salt” in the compound of the present invention, when the compound represented by the general formula (1) is basic, for example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, Examples include salts of inorganic acids such as hydrobromic acid, and salts of organic acids such as acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid, naphthalenesulfonic acid, and camphorsulfonic acid. it can.

In the case where the compound represented by the general formula (1) is acidic, examples thereof include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt, and the like.
Among the compounds represented by the general formula (1), R ¹ and R ² represent phenyl, A represents NR ⁵ , R ⁵ represents isopropyl, D represents butylene, G represents O, R ^The compound 1 or a pharmacologically acceptable salt thereof in which ³ and R ⁴ represent hydrogen and Q is carboxyl is most preferably used.

In addition, among the above compounds, the carboxyl corresponding to Q in the general formula (1) is an equivalent thereof, such as alkoxycarbonyl having 1 to 6 carbon atoms (for example, methoxycarbonyl), tetrazolyl, or the general formula (2). Substituted compounds are also particularly preferably used. In particular, in the general formula (2), R ⁶ is preferably alkyl having 1 to 6 carbon atoms, and compound 2 in which R ⁶ is alkyl having 1 carbon atom (methyl) is particularly preferably used.

  The term “chronic renal failure” in the present invention means that the filtering function of the kidney gradually decreases over time, and the abnormal function state continues for a long time. Specifically, it can be said that blood urea nitrogen (BUN) or serum creatinine level in blood continuously shows a high value or increases or is a syndrome. This definition is essentially equivalent to the textbook definition described in the Background section. More specifically, in the case of humans, when the serum creatinine value measured by the enzyme method is 1.4 mg / dL or more, and this persists for one month or more, it can be reliably determined that chronic renal failure has occurred. In other animal species, the absolute value of the serum creatinine value may be different, but it can be determined that the renal dysfunction has been reached due to the higher value than the normal range.

  In addition, the term “chronic renal failure” in the present invention refers to the stage before chronic renal failure that cannot be maintained unless it is performed by dialysis or kidney transplantation. The present invention can be used particularly effectively in conservative chronic renal failure, although many of the functions performed by the kidney are reduced.

Furthermore, the present invention relates to these indices in the case of animals when the glomerular filtration rate (GFR) measured by creatinine clearance, eGFR, or inulin clearance method is less than 60 mL / min / 1.73 m ^{2 in} humans. Can be used particularly effectively when it drops below 50% of normal. Furthermore, renal function is further lowered, and in the case of humans, it can be preferably used also when it is less than 40 mL / min / 1.73 m ² or less than 30 mL / min / 1.73 m ² .

  The causative diseases of chronic renal failure in the present invention include all renal disorders such as primary kidney disease, systemic kidney disease, congenital kidney disease, kidney infection, kidney damage caused by nephrotoxic substances, and urinary obstruction disease. Disease. Specifically, chronic glomerulonephritis, diabetic nephropathy, chronic pyelonephritis, acute progressive nephritis, pregnancy toxemia, cystic kidney, nephrosclerosis, malignant hypertension, nephropathy associated with various collagen diseases such as SLE, amyloid kidney , Gout kidney, metabolic disorder renal failure, tuberculosis, nephrolithiasis, renal / urinary tract malignant tumor, obstructive urinary tract disease, myeloma, renal dysplasia, etc., but are not particularly limited.

  Renal failure that can be treated (sometimes referred to as “treatment”) according to the present invention is chronic renal failure, particularly conservative chronic renal failure. Not only can the decreased renal filtration function be improved, but it also has an effect of improving cardiovascular disorders and endothelial cell disorders that are particularly problematic in chronic renal failure by improving anemia and increasing SOD activity.

  Anemia in the present invention refers to anemia that develops with chronic renal failure. Specifically, it is possible to determine anemia based on a decrease in the number of red blood cells, hematocrit, hemoglobin amount, etc., and it is known that the number of onset cases increases as the stage progresses after the renal dysfunction stage.

  According to the present invention, anemia associated with chronic renal failure can be prevented or treated, and clinical symptoms such as reduced willingness to work associated with anemia, fatigue, shortness of breath, dizziness on standing, and palpitation can be improved. Furthermore, since it can be administered orally, it can be easily taken every day at home without being accompanied by pain at the time of subcutaneous injection, making it possible to reliably improve anemia and manage various symptoms associated with anemia. .

  For the first time, the improvement effect of the present invention was revealed for the decrease in SOD activity observed in chronic renal failure. Since SOD plays a central role in the reduction / removal of oxidative stress in vivo, it can be expected to improve further reduction in renal function due to an increase in oxidative stress. Furthermore, improvement by the present invention can also be expected for cardiovascular events including vascular and vascular endothelial cell disorders, which are known to increase with chronic renal failure.

  In the present invention, it has been clarified that the decrease in OAT-3, an organic anion transporter of the main excretion pathway of indoxyl sulfate, which is significantly decreased in chronic renal failure and is important as a uremic substance, is suppressed. For this reason, the administration of the compound of the present invention can be expected to suppress the decrease in indoxyl sulfate excretion. Furthermore, it is possible to reduce the side effects of a drug related to excretion by an organic anion transporter, thereby reducing side effects or to easily set an appropriate drug dose.

  Thus, since the compound of the present invention has anemia improvement in chronic renal failure, an increase in renal SOD, and a drug transporter lowering inhibitory effect, it has very favorable characteristics as a drug used for chronic renal failure.

  The compound of the present invention can be produced by a known method, for example, according to the method described in WO2002 / 088084.

In the present invention, to the compounds of the present invention may contain two or more kinds may contain other prostaglandin I ₂ derivative and existing therapeutic agents for renal diseases as described above. Examples of such agents include, for example, angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists, and antihypertensive agents such as calcium blockers and β blockers. In addition, it is also possible to preferably prepare a combination or combination with an antiplatelet drug such as persanthin or dipyridamole, or a statin that has been reported to have a therapeutic effect on renal diseases.

  In addition, since the compound of the present invention can also be used for the treatment of anemia associated with chronic renal failure, it can of course be used in combination with rHuEPO preparations and iron preparations, to prolong the administration interval of rHuEPO preparations and iron preparations and to reduce side effects. Can do. Moreover, it is possible to prepare a mixture with these preparations, or to use a combination with other SOD preparations or oxidative stress inhibitors or to prepare a mixture.

  The present invention is particularly effectively used for mammals. In addition to being used for humans, it can also be used for the treatment of non-human mammals, preferably pets such as dogs, cats, rabbits, rats, and guinea pigs. The present invention can also be used as a therapeutic method for treating chronic renal failure.

  A suitable dose when the therapeutic agent for chronic renal failure of the present invention is used in humans is 1 to 10,000 μg / person per adult as the amount of the compound represented by the above general formula (1) as an active ingredient. The dose is preferably 5 to 5000 μg / person, and is administered once to 4 times a day for 1 day or more, preferably 3 days or more.

  A suitable dose when applied to mammals other than humans is 0.1 μg / kg to 100 mg / kg, preferably 1 μg / kg to 50 mg / kg as the amount of the compound represented by the formula (1) as an active ingredient. kg, and this is administered about once to 4 times a day for 1 day or more, preferably 3 days or more.

  The administration method may be any administration method such as oral administration, subcutaneous administration, intravenous or intravascular administration, intramuscular administration, pulmonary administration, intraduodenal administration, and intraperitoneal administration, and is not particularly limited. Further, a method of directly injecting a drug directly or into a damaged site of a particularly marked tissue or organ in which the drug is contained in an appropriate base is also preferably used.

  In addition, when the chronic renal failure treatment agent of this invention contains the existing renal failure treatment agent as an additional component, the said dosage can be reduced in consideration of the effect of these additional components.

  As the chronic renal failure treatment agent of the present invention, one or several derivatives may be used as they are, but they can also be orally administered in the form of a solid containing the following additives. Examples of additives include excipients such as starches, lactose, sucrose, sucrose, mannitol, calcium carbonate, calcium sulfate and the like: binders such as starches, dextrin, gum arabic, tragacanth, methylcellulose, gelatin, polyvinylpyrrolidone, Polyvinyl alcohol and the like: disintegrating agents such as starches, polyvinyl pyrrolidone, crystalline cellulose and the like, lubricants such as magnesium stearate, talc and the like: coloring agents, fragrances and the like.

  The agent for treating chronic renal failure of the present invention can be used in various dosage forms, specifically, conventionally used dosage forms such as tablets, dragees, powders, granules, troches, capsules, pills, syrups, sprays and the like. Is mentioned. Alternatively, it may be administered parenterally in the form of a bactericidal solution, and other solutes such as sodium chloride or glucose necessary to make the drug solution isotonic can also be used.

  In addition, it is possible to individually control release such as slow release or delayed release depending on the characteristics of each drug. In this case, there are a wide range of methods, both orally and parenterally, such as a method using an implantable sustained-release pump (eg, Alzamini pump) and a method of dispersing in a biodegradable polymer that gradually degrades in the digestive tract. It is possible to take an administration method.

EXAMPLES Hereinafter, the present invention will be described more specifically based on examples, but the present invention is not limited to these examples.
Example 1
Inhibition of platelet aggregation in rats (experimental method)
In order to set a dose at which the PGI ₂ receptor agonist activity is equivalent for the sodium salt of compound 1 and beraprost sodium, the platelet aggregation inhibitory effect, which is a typical pharmacological action of the PGI ₂ receptor agonist, was compared as an index. Rats fasted for 1 day were orally administered with sodium salt of compound 1 (30 mg / kg) or beraprost sodium (0.3 mg / kg), and the time when each plasma concentration peaked, that is, when sodium salt of compound 1 was administered Was collected 1 hour later (Non-patent document: J Pharmacol Exp Ther 322: 1181-1188 2007) and 0.5 hours after administration of beraprost sodium (Non-patent document: Pharmacokinetics 6: 713-725 1989). Induced rat platelet aggregation was measured. Both groups were run with n = 6. Among the PGI ₂ receptor agonists used here, the sodium salt of Compound 1 was synthesized by treating carboxylic acid synthesized according to the method described in Patent Document 4 with sodium hydroxide.
(result)
The inhibition rate for rat platelet aggregation upon stimulation with 10 μM ADP was 47.0 ± 7.9% in the sodium salt administration group of compound 1 and 64.2 ± 8.3% in the beraprost sodium administration group (average of 6 cases in each group). Value ± standard error), and beraprost sodium tended to be stronger, but there was no statistical difference (t test). As a result, it was shown that the 30 mg / kg dose of the sodium salt of Compound 1 exhibited almost the same PGI ₂ receptor activity as the 0.3 mg / kg dose of beraprost sodium.
Example 2
Pharmacological effects in rats with chronic renal failure (experimental method)
Rabbit anti-rat glomerular basement membrane antiserum (14-fold dilution, 3 mL / kg) was intravenously injected into 8-week-old WKY rats to induce glomerulonephritis. Blood was collected 2 weeks after the induction of nephritis, and the serum creatinine level was significantly increased at this time, and it was determined that chronic renal failure had already occurred (normal group: 0.23 ± 0.01 mg / dL, N = 4, nephritis induction group: 0.47 ± 0.01 mg / dL, N = 21, t test). Furthermore, the creatinine clearance used as a glomerular filtration rate (GFR) at this time is 2.63 ± 0.07 mL / min (N = 3) in the normal group, and 1.22 ± 0.04 mL / min (in the nephritis induction group). N = 21). In other words, the creatinine clearance in the nephritis-induced group has decreased to 50% or less of the normal group, and it has been confirmed that chronic renal failure has occurred due to glomerulonephritis, and chronic renal failure has been established 2 weeks after nephritis induction. It was time. The creatinine clearance of the control group at 6 weeks after induction of nephritis was 0.33 ± 0.10 mL / min, which was 10.2% of the normal group (3.24 ± 0.13 mL / min). This stage is the time to consider introducing dialysis in humans and corresponds to the most severe stage of conservative renal failure.

  Therefore, the normal group (no nephritis induction and administration, n = 4), the control group (administration of solvent alone, n = 7), compound 1 based on the serum creatinine value in rats with chronic renal failure 2 weeks after nephritis induction Sodium salt group (30 mg / kg administered twice a day, n = 7) and beraprost sodium group (0.3 mg / kg administered twice a day, n = 7). The administration was started and thereafter administered every day. At this time, a 0.25% sodium carboxymethyl cellulose solution was used as a solvent for the drug.

  Urine and blood were collected appropriately from 2 weeks to 6 weeks after nephritis induction when chronic renal failure was established, and the serum creatinine value, BUN, and creatinine clearance in each group were measured to evaluate renal function. In addition, hematocrit value, hemoglobin amount, and SOD activity of kidney tissue, which are closely related to the pathology of chronic renal failure, were measured, and the mRNA expression level of organic anion transporter OAT-3 was quantified. SOD activity was measured using SOD assay kit WST (Dojindo Laboratories), and OAT-3 mRNA expression level was quantified using LightCycler Fast Start DNA Master SYBR Green I (Roche).

Statistical analysis was performed 6 weeks after nephritis induction in which the control group progressed at a severe stage of preservation stage renal failure. Statistical differences are determined by the Barlett test between the control group and each drug group, and the parametric Dunnett test is performed between each drug group and the control group in the case of equal variance. A parametric Dunnett test was performed and the risk rate was set to less than 5%.
(Result 1)
As shown in FIG. 1, the serum creatinine value of the sodium salt group of Compound 1 remained low relative to the control group until 6 weeks after nephritis induction. As shown in FIG. 2, the BUN in the sodium salt group of Compound 1 remained at a low level compared to the control group until 6 weeks after nephritis induction. As shown in FIG. 3, the creatinine clearance in the sodium salt group of Compound 1 remained high compared to the control group until 6 weeks after nephritis induction. Furthermore, the creatinine clearance of the sodium salt group of Compound 1 at 6 weeks after induction of nephritis is significantly higher than that at the start of administration (2 weeks after induction of nephritis) (after 2 weeks: 1.21 ± 0.06 mL / min). 6 weeks later: 1.48 ± 0.11 mL / min, t test), Compound 1 sodium salt not only suppresses the progression of chronic renal failure but also has a clear improvement effect on renal filtration function It was done.

  Table 1 shows the results of comparing the effects of each drug 6 weeks after induction of nephritis. The serum creatinine value of the sodium salt group of Compound 1 was significantly lower than that of the control group, but the serum creatinine value of the beraprost sodium group was not statistically different from the control group ( Nonparametric Dunnett test). The BUN of the sodium salt group of Compound 1 was significantly lower than that of the control group, but the BUN of the beraprost sodium group was not statistically different from that of the control group (nonparametric Dunnett test). ). The creatinine clearance of the sodium salt group of Compound 1 was significantly higher than that of the control group, and the creatinine clearance of the beraprost sodium group was also significantly higher than that of the control group (parametric Dunnett test).

  From the above results, it was shown that the sodium salt of Compound 1 is superior in improving renal function compared to beraprost sodium.

(Result 2)
The hematocrit value (32.0 ± 2.09%) and the hemoglobin amount (11.8 ± 0.69 g / dL) of the control group 6 weeks after nephritis induction were the normal group (hematocrit value 44.1 ± 0.34%), respectively. , The amount of hemoglobin 16.0 ± 0.09 g / dL)) was significantly reduced (t test, p <0.05). Similar to other rats with glomerulonephritis (Non-patent document: Mol Med 4: 413-424 1998) and ICGN mice (Non-patent document: J Vet Med Sci 66: 423-431 2004) that spontaneously develop renal anemia. Therefore, it was determined that renal anemia was also reached in this chronic renal failure rat. As shown in Table 2, the hematocrit value and the amount of hemoglobin in the sodium salt group of Compound 1 were significantly higher than those in the control group. The hematocrit value and the amount of hemoglobin in the beraprost sodium group were higher than those in the control group, but no statistical difference was observed (nonparametric Dunnett test). From the above, it was suggested that the sodium salt of Compound 1 has an anemia improving action.

(Result 3)
Table 3 shows the measurement results of the SOD activity of the renal tissue 6 weeks after nephritis induction. The SOD activity of the sodium salt group of Compound 1 was significantly higher than that of the control group. Although the SOD activity of the beraprost sodium group was higher than that of the control group, no statistical difference was observed (parametric Dunnett test). From the above, it was suggested that the sodium salt of Compound 1 has an oxidative stress improving action by increasing SOD activity.

(Result 4)
Table 4 shows the quantification results of mRNA of the organic anion transporter OAT-3 expressed in the renal cortex 6 weeks after nephritis induction. The amount of OAT-3 expressed in the sodium salt group of Compound 1 was significantly higher than that in the control group. The expression level of OAT-3 in the beraprost sodium group was higher than that in the control group, but no statistical difference was observed (parametric Dunnett test). That is, it was suggested that the sodium salt of Compound 1 has an action of improving the excretion of uremic substances by suppressing the decrease in OAT-3 which is a transporter.

Example 3
Changes in plasma concentration of compound 1 when compound 1 and compound 2 were administered to rats Compound 1 or compound 2 was orally administered to rats at 5 mg / kg and compound 1 was intravenously administered at 1 mg / kg. The concentration of Compound 1 was measured. Both groups were tested at n = 3. Compound 2 is converted to Compound 1 in vivo, and there is no statistical difference in bioavailability compared to when Compound 1 is administered directly (Table 5). As shown in FIG. Since the transitions almost overlapped, it was shown that Compound 2 can be used in the same manner as Compound 1. Compound 1 and Compound 2 used here were synthesized according to the method described in Patent Document 4.

As described above, the sodium salt of Compound 1 and beraprost sodium at doses that are approximately the same as PGI ₂ receptor agonist were orally administered to rats with chronic renal failure to examine the treatment effect in chronic renal failure. As a result, the sodium salt of Compound 1 has superior effects compared with beraprost sodium in improving renal function, improving anemia, improving SOD activity, and improving the decrease in OAT-3 related to excretion of uremic substances. I understood. Therefore, it was shown that the compound of the present invention represented by the sodium salt of Compound 1 is extremely useful as a therapeutic agent for chronic renal failure compared to other known compounds.

Claims (7)

The following general formula (1)

[Wherein R ¹ and R ² each independently represent aryl,
A represents NR ⁵ , O, S, SO or SO ₂ ;
R ⁵ represents alkyl having 1 to 6 carbons, alkenyl having 2 to 6 carbons or cycloalkyl having 3 to 6 carbons;
D represents alkylene or alkenylene having 2 to 6 carbon atoms,
G represents O, S, SO or SO ₂ ;
R ³ and R ⁴ each independently represent hydrogen or alkyl having 1 to 6 carbons,
Q is carboxyl, alkoxycarbonyl having 1 to 6 carbon atoms, tetrazolyl, or the following general formula (2)

(In the formula, R ⁶ represents alkyl having 1 to 6 carbon atoms.)
Represents. ]
Or a pharmacologically acceptable salt thereof as an active ingredient. R ¹ and R ² represent phenyl,
R ⁵ represents alkyl having 1 to 6 carbon atoms,
D represents alkylene having 2 to 6 carbon atoms;
G represents O,
R ³ and R ⁴ represent hydrogen,
Q represents carboxyl or general formula (2),
The therapeutic agent for chronic renal failure according to claim 1. A represents NR ⁵ ;
R ⁵ represents a branched alkyl having 3 to 6 carbon atoms,
D represents butylene,
Q represents carboxyl or general formula (2),
The chronic renal failure treatment agent according to claim 1 or 2. R ⁵ represents isopropyl,
Q represents carboxyl or general formula (2),
The chronic renal failure treatment agent according to any one of claims 1 to 3. Q represents carboxyl;
The chronic renal failure treatment agent according to any one of claims 1 to 4. The chronic renal failure treatment agent according to any one of claims 1 to 5, wherein the chronic renal failure is in a preservation period. The therapeutic method for chronic renal failure treatment using the compound as described in any one of Claim 1 to 5, or its pharmacologically acceptable salt.

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